Benefits of Pioglitazone In Patients with Prediabetes Who Had a Stroke

Pioglitazone shown to be effective for secondary prevention in patients who have had a stroke and have prediabetes, according to a post hoc analysis of the IRIS trial.

According to a review article by W.N. Kernan, et al, published in the Journal of Neurology, insulin resistance has been associated with a 60% to 160% increased risk for stroke in patients who do not have diabetes. Insulin resistance is present in most patients with type 2 diabetes. It is also common among elderly persons, certain ethnic groups, and persons with hypertension, obesity, physical deconditioning, and vascular disease. Insulin resistance may be a prevalent risk factor for stroke. New drugs can safely reduce insulin resistance and may have a role in stroke prevention.

The post hoc analysis of the IRIS randomized multicenter clinical trial was performed from June to September 2018 and published online on February 7, 2019 in JAMA neurology. The objective was to analyze the effects of pioglitazone in patients who followed their medication regimens as well as the intention to treat effects of pioglitazone in patients with prediabetes in the IRIS trial.

To assist in translating the IRIS trial results to real world practice, prediabetes was defined per American Diabetes Association criteria as having a hemoglobin A1c level of 5.7% to 6.4% or fasting plasma glucose level of 100 mg/dL to 125 mg/dL. Also, maintaining a regimen was defined as taking 80% or more of the protocol dose over the duration of the study. The primary outcome was recurrent stroke or MI. Secondary outcomes included stroke, acute coronary syndrome, stroke/MI/hospitalization for heart failure, and progression to diabetes.

By the American Diabetes Association criteria, there were 2,885 participants with prediabetes who were included in the analysis. Participants with prediabetes had higher levels of glycosylated HbA1c than those without prediabetes and higher Homeostatic -IR scores, the latter indicating greater insulin resistance. Pioglitazone reduced stroke/MI by 40%, stroke by 33%, acute coronary syndrome by 52%, and new-onset diabetes by 80% over a median follow-up of 4.8 years. Intention-to-treat results also showed significant reduction of events but to a lesser degree. These findings were observed despite a higher proportion of men and smokers, higher diastolic blood pressures, and lower high-density lipoprotein cholesterol levels among individuals who followed their medication regimen and were assigned to receive pioglitazone.

There was a nonsignificant reduction in overall mortality, cancer, and hospitalization, a slight increase in serious bone fractures, and an increase in weight gain and edema.

The benefit of pioglitazone continued to increase over time, suggesting that even greater benefits might have been shown with longer follow-up. Some or much of this may have been due to prevention of diabetes over time.

The study concluded that pioglitazone appears to reduce the risk of recurrent stroke or MI, recurrent stroke, acute coronary syndrome, and diabetes in patients with insulin resistance and prior stroke/transient ischemic attack and prediabetes, particularly in individuals who adhere to therapy. These benefits appear to outweigh the risks of fracture and fluid retention.

In a systemic review and meta-analysis of three randomized controlled trials with 4,980 participants by M. Lee, et al found that use of pioglitazone in patients who had had a stroke and have insulin resistance, prediabetes, and diabetes mellitus was associated with lower risk of recurrent stroke and future major vascular events. There was no evidence of an effect on all-cause mortality and heart failure.

Though this meta-analysis showed no evidence of an effect on all-cause mortality and heart failure and showed promising effects as a secondary prevention treatment, pioglitazone still is not approved as a secondary stroke prevention treatment.

Practice Pearls:

Pioglitazone appears to reduce the risk of recurrent stroke or MI, recurrent stroke, acute coronary syndrome, and diabetes in patients with insulin resistance and prior stroke/transient ischemic attack and prediabetes, particularly in individuals who adhere to therapy.

Recent studies have shown that these benefits appear to outweigh the risks of fracture and fluid retention and that there is no evidence of an effect on all-cause mortality and heart failure.

Pioglitazone is still not approved as a secondary stroke prevention treatment and further studies that support it are needed.